The general goal of our work is to further the understanding of the relation between structure and fuction in biological molecules. The proposal focuses on the energetics of solvation effects in a range of biologically important systems. The approach we develop and apply is based on a macroscopic description of solvent already averaged over its microscopic states. It assumes that the total enthalpy of hydration is the sum of the enthalpy of electrostatic interactions of the molecule with the solvent and of the hydration enthalpy of a nonplar molecule forming the same cavity in the solvent. A new reaction field treatment of the solute-solvent interactions with a self-consistent definition of the boundary between the solute and the solvent are used to calculate the electrostatic contribution to the enthalpy. Quantum chemical or semiempirical fitting procedures are used to describe the charge distribution of the solute. Improved representation of the charge distributions as well as improved calculations with large basis sets are being introduced and explored. The non-electrostatic contributions to the hydration enthalpy are introduced through interpolation of experimental results or results of the scaled particle theory for nonpolar molecules. Empirical correlations and simple statistical mechanical calculations will serve in the evaluation of hydration entropy to obtain free energies of hydration. The methods will be tested by applications to systems for which solvation effects have been measured experimentally. These include the solvation energies of small ions and a variety of polar molecules, pK differences in neurotransmitters and proteins, and energies of transfer between water and other polar or non polar solvents. Planned applications to other systems in which solvation effects are likely to be important include calculations on hydrogen bonding, ionic association, ion binding to carriers, helix-coil transitions, and the electrostatic effects on the rate of hydrogen exchange on the surface of proteins.